1. Field in the Industry
The present invention concerns a process for preparing optically active 3-(methylamino)-1-(2-thienyl)propan-1-ol (hereinafter abbreviated as “MMAA”). The present invention concerns also novel diastereomeric salts obtained as the intermediates in the process for preparing the optically active MMAA. The optically active MMAA prepared by the present process is an important intermediate for synthesis of pharmaceuticals, particularly, for a new drug “Duloxetine” (EP273658) which is expected to be a useful pharmaceutical for treating depression and urinary incontinence.
2. Prior Art
For the preparation of Duloxetine the following synthesis route has been known. Optically active 3-(dimethylamino)-1-(2-thienyl)propan-1-ol (herein-after abrreviated as “DATP”) is condensed with a naphthalene to form a naphthyl derivative, followed by demethylation to give Duloxetine (Chirality in industry II, p. 101–104 (1997); John Wiley & Sons: Yew York).

As the methods to carry out the above demethylation there has been known to treat the naphthyl derivative with trichloroacetyl chloride (Japanese Patent Disclosure 04-226948(1992), Tetrahedron Lett., 31(49), 7101 (1990)), or with phenoxycarbonyl chloride (Japanese Patent Disclosure 07-188065(1995)). These known methods, however, have such drawbacks that trichloroacetyl chloride itself is harmful, that the yield of synthesis is low, and that partial racemization occurs during the reaction. In other words, as far as the preparation method through the dimethylation route is applied, it cannot be avoided that the yield is low and the optical purity decreases due to the racemization during the step.
On the other hand, if MMAA, which is demethylated derivative of DATP, is used as the intermediate for preparation of Duloxetine, demethylation step is unnecessary, and it can be expected that condensation of MMAA with a naphthalene compound according to the known methods (such as that of EP273658) may easily give Duloxetine without any deterioration caused by demethylation step, as shown below.

In case where the optical resolution accompanies the preparation of Duloxetine, recovered (R)-MMAA from the mother liquor can be racemized by an ordinary racemization method and recycled to the next batch of the resolution step.
To date, however, there has not been known process for preparing optically active MMAA by optical resolution. Having noted this fact the inventors made research intensively on the optical resolution of MMAA and succeeded to develop a new resolution process suitable for a commercial scale production.